Epothilones are a relatively new class of macrolide compounds that were originally obtained by fermentation of myxobacteria (Sorangium cellulosum). These compounds were initially investigated as plant protective agents due to their anti-fungal properties. Epothilones then became of interest due to their cytotoxic activity on animal cells, and were subsequently characterized as tubulin polymerization agents. It is now known that epothilones exert microtubule-stabilizing effects similar to paclitaxel (TAXOL®) and cytotoxic activity against rapidly proliferating cells such as tumor cells or other hyperproliferative cellular disease. The use of epothilones as chemotherapeutic agents is described in Bollag et al., Cancer Research 55, 2325, 1995.
Epothilones A and B (epo A or epo B, respectively) have the structures,
                Epothilone A R═H        Epothilone B R═Me        
One scheme for obtaining epothilones was revealed by Höfle et al. in WO 93/10121. Höfle cultured a strain of Sorangium cellulosum in a medium containing carbon sources, nitrogen sources and mineral salts. An adsorber resin was added during the culturing of the strain. The epothilones were eluted with solvent from the adsorbent resin. The various epothilones were separated by reverse-phase chromatography and crystallized. However, Höfle et al. conceded that this method produced only a low quantity of epothilone B, and also that the ratio of epothilone B to epothilone A in the fermentation was low. This low ratio of epothilone B relative to epothilone A makes recovery of pure epothilone B difficult. Thus, there is a need in the art for improved methods of fermentation to produce epothilone B in preference to epothilone A, and improved methods of isolation and purification of epothilone B.